ABSTRACT:ThisRFA-MH-17-405?AdultMaturationalChangesandDysfunctionsinEmotionRegulation?R01 proposalisdesignedtostudyage-relatedchangesinstructureandfunctionofaventralprefrontalcortex (VPFC)neuralsystem,thatsubservesemotionprocessingandregulation,duringmidtolateradulthoodin individualswithbipolardisorder(BD),comparedtohealthycontrol(HC).TheemotionaldysregulationofBD, fromtheextremepositivemoodstatesofmaniastonegativeofdepressions,isassociatedwithagreatdealof sufferingforthoseaffectedandtheirfamilies,withearlymortalityowingtooneofthehighestratesofsuicidein anydisorder.Progresshasbeenmadebyourandotherresearchgroupsintheidentificationofabnormalities intheVPFCbraincircuitrythatsubservesemotionalregulationascentraltothedisorderanditsemotional dysregulation.BDischronicandoftenprogressesduringmiddletolateadulthood,withanincreasein emotionaldysregulation,episodefrequencyandseverity,andsymptomsthatcanbecomeincreasingly refractorytocurrenttreatments,increasingsuiciderisk.However,therehasbeenlittlepreviousstudyofthe braincircuitrychangesthatunderliethisprogression.Ourexcitingnewpreliminarydataimplicateprogressive decreaseswithageinolderadultswithBDwithinemotionalbraincircuitryinthestructuralintegrityofgray matterregionsandtheirwhitematterconnections,andtheabilityofnodeswithinthecircuitrytoworkwell togethertoregulateemotionalresponses.Inthefirstsuchworkweareawareof,weplantobuildonour previousneuroimagingandbehavioralresearchinBDtostudytheseage-relatedemotionalbraincircuitry changesinolderadults.Weproposea5-yearstudyofage-relatedchangesinmood,emotionregulationand relatedsymptomsandbehaviorsusingmultimodalityimagingmeasures[structuralmagneticresonance imaging(MRI)ofgraymatter,diffusiontensorimaging(DTI)ofwhitematter,andfunctionalMRI(fMRI) measuresoffunctionalconnectivityandofbrainresponsesduringimplicitandexplicitemotionregulation] comparingBDandHCgroups(N=80/group),ages40-79years,50%female;?64individuals/groupwillbe reassessedandrescannedafter2yearstostudybrainandassociatedbehavioralchangesovertime.Wewill explorerelationshipsbetweenbrainagingwithsexdifferences,andwithriskfactorsimplicatedinprogression includinggenesandstress,aswellasadverseoutcomesofprogressionsuchassuicideideationandbehavior. AstherehasbeenlittlestudyofeffectsofagingoftheVPFCemotionalcircuitryinhealthyindividuals,findings couldprovidenewinsightsintobraincircuitryandemotionalregulationinolderadults.Inadditiontothe importanceofcontributingtounderstandingBD,asBDisuniqueinhavingbothelevatedanddepressive episodes,itsstudycanprovideamodelforunderstandingprogressiveemotiondysregulationtobothnegative andpositiveextremes.Identificationofage-relatedbrainchangesinBDcouldprovidenoveltargetsfor interventionandpreventionthatcanbebettertargetedspecificallyforolderindividualswithBD.